There is a fundamental gap in understanding how to design penetrating microstimulation for neuroprostheses, particularly with consideration to the tissue response to device insertion and/or the application of the electrical stimulation. Our long-term goal is to develop multi-channel microstimulation of central nervous tissue for clinical therapy. The overall objective of the proposed research is to identify the optimal stimulation parameters for a chronically-implanted microstimulation device. In particular, our objective focuses on the effects of repeated stimulation and the reactive tissue response on the efficacy of stimulation-driven activity. Our central hypothesis is that multi-channel microstimulation will be a more effective treatment than low-channel count macrostimulation. The rationale that underlies the proposed research is that, once the optimal stimulation parameters are known for a given level of tissue response, microstimulation-based devices can be designed and tested for chronic disease treatment. Thus, the proposed research is relevant to the translational focus of the NIH's mission and will potentially help to reduce the burdens of human disability. This hypothesis will be tested by pursuing two specific aims: first we will study how different microstimulation parameters affect the psychophysical threshold and the dynamic range for sensation. Psychophysical experiments will be performed using multi-channel cortical implants in the auditory cortex of rats. Second, we will investigate is the effect of the device-tissue interfacial quality on the psychophysical threshold. Chronic implantation of neural implants is followed by a reactive tissue response that both functionally isolates the electrode from the tissue as well as triggers neuronal apoptosis and migration. We will measure these functional changes and determine their role in modulating the efficacy of a cortical auditory prosthesis. The approach is innovative because of the combination of simultaneous behavioral, electrochemical and electrophysiological assessment. The proposed research is significant because it will establish feasibility and practicality for utilizing microstimulation to develop therapies. These therapies will enable neuroprosthetic development for many potential applications of microstimulation. PUBLIC HEALTH RELEVANCE: The proposed studies are in the area of microstimulation for neuroprostheses, which has potential applications in many human diseases or injuries. Our findings will provide fundamental data enabling design of efficacious neuroprostheses. Thus, the proposed research is relevant to the translational focus of the NIH's mission and will potentially help to reduce the burdens of human disability.